Conventional medications for the management of systemic autoimmune diseases are often associated with long-term side-effects. This has spurred research into alternative or complementary treatment modalities for these diseases, including systemic lupus erythematosus. Based on its efficacy in several other chronic diseases, the Ayurvedic supplement, curcumin holds great promise in lupus treatment - however, this has never been tested directly. Our recent work in mouse models has uncovered at least 3 major checkpoints in lupus development - breach in lymphocyte tolerance to self antigens, amplification of the autoimmune process by hyperactive, pro-inflammatory dendritic cells, and end-organ inflammation, affecting the kidneys in particular. Genetically simplified mouse models have recently been generated, encompassing these individual checkpoints. The goal of this application is to use these novel genetic models to understand if and how curcumin might impact immune tolerance, dendritic cell function and/or end-organ inflammation. Dissecting out the mechanism of action of alternative therapeutic regimes in autoimmunity will allow us to eventually optimize complementary treatment strategies for lupus, tailored to the genetic makeup of the patient. PUBLIC HEALTH RELEVANCE: Conventional medications for the management of SLE are often associated with long- term side-effects. In this context, "natural supplements" may be particularly useful if proven effective. Based on its efficacy in several other chronic diseases, the Ayurvedic supplement, curcumin holds great promise in lupus treatment. The proposed studies will ascertain the precise check-points and mechanisms of action through which curcumin might work in lupus. The findings from this study could have a profound impact on how we use natural supplements in treating human SLE in the future.